Osteogenic implants with combined implant materials and methods for same

ABSTRACT

Described are osteogenic implants that include a first implant material covered at least in part by a second implant material carrying an osteogenic protein such as a bone morphogenic protein. The first implant material can comprise a mineral and provide an inner scaffolding portion for supporting bone ingrowth, and the second implant material can comprise a collagen or other sponge carrier covering the first implant material and having a liquid osteogenic protein formulation imbibed therein. Related implant materials and methods of preparation and use constitute additional aspects of the invention.

REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 11/118,124 filed Apr. 29, 2005, which claims the benefit ofU.S. Patent Application Ser. No. 60/611,527 filed Sep. 20, 2004, each ofwhich is hereby incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

The present invention resides generally in the field of implants forpromoting bone growth, and in one particular aspect the inventionrelates to implants for promoting bone growth that contain an osteogenicprotein combined with a porous matrix material.

As further background, a wide variety of therapeutic regimens areundertaken to induce the growth of bone of a patient into a desiredregion. Examples of such therapeutic regimens exist in the field ofspinal surgery, including a variety of spinal fusion procedures.Illustratively, in posterolateral fusion procedures, bone growth isinduced to fuse transverse processes of adjacent vertebrae, typically inthe lumbar spine. In the predominant historic and current practice, boneof the patient harvested from the iliac crest is implanted betweentransverse processes of the patient to facilitate the growth of a bonemass sufficient to achieve arthrodesis. However, increased costs andrisks are associated with the harvest of the patient's bone, and in somepatients there may be insufficient quality iliac crest bone for theprocedure. Consequently, more recent efforts in academics and industryhave explored the development of procedures that minimize or eliminatethe need to harvest patient bone.

In certain areas of study, implants including osteogenic proteins havebeen used instead of or as a supplement to autogeneous bone. The use ofsuch osteogenic proteins is itself accompanied by a variety ofchallenges. The active protein materials are commonly complicated toobtain or produce, costly, and highly regulated. As well, challenges arepresented in determining the optimal and most effective use of theosteogenic proteins to generate relevant masses of bone for fusion orother purposes.

In light of this background, there remain needs for improved and/oralternative osteogenic implant materials as well as related materialsand methods for their preparation and use. The present invention isaddressed to these needs.

SUMMARY OF THE INVENTION

In certain aspects, the present invention features the discovery of anosteogenic implant configuration that effectively utilizes osteogenicprotein to induce bone growth through a desired volume occupied by theimplant. Accordingly, in one embodiment, the present invention providesan osteogenic implant for promoting bone growth between first and secondbone surfaces. The implant includes a first resorbable implant materialdefining an implant body configured for receipt between the first andsecond bone surfaces. The first resorbable implant material includes aporous collagenous matrix containing mineral particles. The osteogenicimplant also includes a second resorbable implant material covering atleast a portion of the outer surface of the implant body, wherein thesecond material is positioned to contact the first and second bonesurfaces. The osteogenic implant further includes an osteogenic proteincarried by the second resorbable implant material. In certainembodiments, the osteogenic implant is configured for receipt betweenadjacent upper and lower transverse processes in the spine of a mammal,including a human, and/or the osteogenic protein is a bone morphogenicprotein (BMP) such as BMP-2, BMP-4, BMP-6, or BMP-7. As well, themineral particles can comprise bone, a synthetic ceramic material, orcombination thereof.

Another embodiment of the invention provides a medical implant forpromoting bone growth, the medical implant having an outer osteogenicimplant material, the outer osteogenic implant material including awetted, porous bioresorbable sponge matrix having sorbed therein anaqueous medium including an osteogenic protein. The implant alsoincludes an inner scaffolding implant material including a mineralcomponent such as an osteoconductive synthetic ceramic, the innerscaffolding implant material configured to occupy a three-dimensionalvolume for bone ingrowth initiated by the outer osteogenic implantmaterial.

In another embodiment, the invention provides an implant configured topromote spinal fusion between first and second transverse processes in apatient. The implant includes a first resorbable implant materialdefining an implant body configured for receipt between the first andsecond transverse processes, wherein the first resorbable implantmaterial includes a porous collagen-containing matrix incorporatingmineral particles. A collagen sponge carrier covers at least a portionof the outer surface of the implant body and is positioned to contactthe first and second transverse processes. A bone morphogenic protein iscarried by the collagen sponge carrier.

In another embodiment, the invention provides an implant for promotingbone growth between first and second bone surfaces. The implant includesa first implant material containing collagen and mineral and configuredto occupy a volume for bone growth. The implant further includes asecond implant material covering at least a portion of the first implantmaterial, wherein the second implant material carries an osteogenicprotein.

In another aspect, the invention provides an implant suitable forcarrying an osteogenic protein. The implant includes a first resorbableimplant material defining an implant body and configured for receiptbetween first and second bone surfaces. The first resorbable implantmaterial includes a mineral component, and can be a porous resorbablematrix incorporating mineral particles. A second resorbable implantmaterial is provided a covering at least a portion of the outer surfaceof the implant body and is positioned to contact the first and secondbone surfaces. In certain embodiments, the implant can be configured foruse in a spinal fusion procedure in a mammal such as a human, includinga posterolateral spinal fusion procedure. The first resorbable implantmaterial can for example include a porous collagen-containing matrixincorporating mineral particles, and/or the second resorbable implantmaterial can include a collagen sponge carrier.

Still another embodiment of invention provides a medical kit forpromoting bone growth between first and second bone surfaces of apatient. The medical kit includes a first resorbable implant materialcomprising a mineral component such as a porous resorbable matrix havingparticulate mineral embedded therein. The kit further includes a secondresorbable implant material configured to cover at least a portion of asurface of the first resorbable implant material, and an osteogenicprotein. The kit can include other components such as one or moresyringes, surgical tools, and/or surgical implants.

In another embodiment, the invention provides a method for preparing amedical implant for inducing bone growth in a patient at an implantsite. The method includes the steps of providing (i) a dry, porousbioresorbable sponge matrix; (ii) an osteoconductive scaffoldingmaterial comprising a mineral component; and (iii) an aqueousformulation including an osteogenic protein. The dry, porousbioresorbable sponge matrix is wetted with the aqueous formulation so asto form a wetted bioresorbable sponge matrix having the aqueousformulation sorbed therein, and at least a portion of theosteoconductive scaffolding material is covered with the wettedbioresorbable sponge matrix.

The invention provides in another embodiment a method for inducingspinal fusion between first and second bone surfaces in a patient. Themethod includes providing (i) a dry, porous bioresorbable sponge matrix;(ii) an osteoconductive scaffolding material comprising a mineralcomponent; and (iii) an aqueous formulation including an osteogenicprotein. The dry, porous bioresorbable sponge matrix is wetted with anaqueous formulation so as to form a wetted bioresorbable sponge matrixhaving the aqueous formulation sorbed therein. The wetted bioresorbablesponge matrix is manipulated to cover at least a portion of theosteoconductive scaffolding material and form a combined implantconstruct. The combined implant construct includes first and secondportions of the wetted porous sponge matrix positioned to contact thefirst and second bone surfaces, respectively, the combined implantconstruct further having the osteoconductive scaffolding materialpositioned between the first and second portions of the wettedbioresorbable sponge matrix. The method further includes implanting thecombined implant construct between the first and second bone surfaces inthe patient with the first and second portions of the wetted poroussponge matrix contacting the first and second bone surfaces and theosteoconductive scaffolding material occupying a volume for bone growthto create a fusion mass between the first and second bone surfaces.

In still further embodiments, the present invention provides furthermethods of preparing and using implants of the invention as describedhereinbelow.

Additional embodiments as well as features and advantages of theinvention will be apparent from the descriptions herein.

DESCRIPTION OF THE FIGURES

FIG. 1 provides a perspective view of first and second resorbableimplant materials used to prepare an implant of the invention.

FIG. 2 provides a cross-sectional view of an implant of the inventionincluding first and second resorbable implant materials.

FIG. 3 provides a view of an implant of the invention configured forposterolateral fusion received between first and second transverseprocesses of a human patient.

FIG. 4 provides a perspective partial cutaway view of another combinedimplant construct of the invention.

DETAILED DESCRIPTION

For the purposes of promoting an understanding of the principles of theinvention, reference will now be made to certain embodiments thereof andspecific language will be used to describe the same. It willnevertheless be understood that no limitation of the scope of theinvention is thereby intended, and alterations and modifications in theillustrated implants, and further applications of the principles of theinvention as illustrated herein are contemplated as would normally occurto one skilled in the art to which the invention relates.

As disclosed above, one aspect of the present invention providesosteogenic implants that include a first implant material having asurface covered at least in part by a second implant material, whereinthe second implant material incorporates an osteogenic protein such as abone morphogenic protein (BMP). In other aspects, the invention providesmaterials and methods for preparing and using osteogenic implants.

Implants of the invention include a first implant material including anatural and/or synthetic mineral component. For example, the mineralcomponent can be provided by a particulate mineral material, includingeither powder form or larger particulate mineral materials such asgranules. In certain embodiments, the particulate mineral component iseffective in providing a scaffold for bone ingrowth as the resorbablematrix material is resorbed. The mineral material may for example bebone, especially cortical bone, or a synthetic bioceramic such as acalcium-containing ceramic, for example a biocompatible calciumphosphate ceramic. Illustrative ceramics thus include tricalciumphosphate, hydroxyapatite, and biphasic calcium phosphate. These mineralcomponents may be purchased commercially or obtained or synthesized bymethods known in the art. Mineral components of inventive implants canalso serve as a source of calcium and/or phosphate ions for bonegeneration and can be incorporated at levels to regulate thecompressibility of the implants.

As noted above, biphasic calcium phosphate can be used to provide themineral component in the invention. Desirably, such biphasic calciumphosphate will have a tricalcium phosphate:hydroxyapatite weight ratioof about 50:50 to about 95:5, more preferably about 70:30 to about 95:5,even more preferably about 80:20 to about 90:10, and most preferablyabout 85:15.

The first implant material can include an amount of mineral that willprovide a scaffold effective to remain in the patient for a period oftime sufficient for the formation of osteoid in the void for which bonegrowth is desired. Typically, this period of time will be about 8 toabout 12 weeks, although longer or shorter periods may also occur inparticular situations. The minimum level of mineral that must be presentin the composition is also dependent on the activity of the BMP or otherosteogenic protein in the composition. Generally, the higher theactivity of the protein, the greater the content of the mineral matrixrequired.

In certain embodiments of the invention, the first implant materialincludes a plurality of discrete mineral particle such as granules ormay be provided by a monolithic synthetic ceramic or other mineral bodydimensioned to occupy the desired three dimensional space for boneingrowth. In other embodiments of the invention, the first implantmaterial includes a porous matrix material incorporating mineralparticles. The porous matrix material can be collagenous. A wide varietyof collagen materials are suitable for these purposes. Naturallyoccurring collagens may be subclassified into several different typesdepending on their amino acid sequence, carbohydrate content andpresence or absence of disulfide cross-links. Types I and III collagenare two of the most common subtypes of collagen. Type I collagen ispresent in skin, tendon and bone whereas Type III collagen is foundprimarily in skin. The collagen in the matrix may be obtained from skin,bone, tendon, or cartilage and purified by methods known in the art.Alternatively, the collagen may be purchased commercially. The porousmatrix composition desirably includes Type I bovine collagen.

The collagen of the porous resorbable matrix can further be atelopeptide collagen and/or telopeptide collagen. Moreover, bothnon-fibrillar and fibrillar collagen may be used. Non-fibrillar collagenis collagen that has been solubilized and has not been reconstitutedinto its native fibrillar form.

The resorbable matrix of the first implant material may also be formedof other natural or synthetic polymeric materials, in addition to or asan alternative to collagen. For example, the resorbable matrix maycomprise gelatin (e.g. foamed gelatin), or resorbable synthetic polymerssuch as polylactic acid polymers, polyglycolic acid polymers, orco-polymers thereof. Other natural and synthetic polymers are also knownfor the formation of biocompatible resorbable matrix materials, and canbe used in the invention.

In certain forms of the invention, the first implant material will havea particulate mineral:resorbable porous matrix weight ratio of at leastabout 4:1, more typically at least about 10:1. In highly mineralizedimplants, the particulate mineral will constitute at least 95% by weightof the first implant material. For example, highly effective firstimplant materials are provided wherein they comprise about 97% to about99% by weight particulate mineral and about 1% to about 3% of thecollagen or other matrix forming material. Moreover, the mineralcomponent in certain embodiments has an average particle size of atleast about 0.5 mm, more preferably about 0.5 mm to about 5 mm, and mostpreferably about 1 mm to about 3 mm.

To make one form of the first implant material, a collagen slurry may beprepared as known, and can be chilled to increase its viscosity to helpsuspend the particulate mineral component. The particulate mineral isdispersed into the collagen slurry and gently mixed. After theparticulate mineral component is uniformly dispersed in the slurry, theslurry is poured into sterile trays or other forms and freeze dried. Thesheets of implant material are then removed from the freeze drier and ifdesired exposed to a glutaraldehyde or other cross-linking agent. Thecomposite material formed is desirably three-dimensionally stable butflexible, and can be sterilized and packaged in accordance with knownprocedures.

As noted above, osteogenic implants of the invention include a secondresorbable implant material covering at least a portion of the surfaceof the first resorbable implant material. The second implant materialcan include a porous matrix prepared with a matrix-forming material suchas those discussed above for the first implant material. Accordingly,the second implant material may include a resorbable collagenous matrixin certain embodiments, which may incorporate any of the collagen typesdiscussed above or any combination thereof. In a particular embodiment,the second implant material may be provided by an absorbable collagensponge (ACS) material made with Type 1 bovine collagen and manufacturedby Integra Lifesciences. As well, the resorbable matrix in the secondimplant material may also be formed of other natural or syntheticpolymeric materials in addition to or as an alternative to collagen.Such materials may for example include gelatin or other natural orsynthetic polymers (e.g. polylactic acid, polyglycolic acid, orcopolymers thereof) useful for the formation of biocompatible resorbablematrix materials. The second resorbable implant material may alsoinclude a mineral component, which may be the same as or different fromthat of the first resorbable implant material.

As indicated above, osteogenic implants of the invention include anosteogenic protein carried in the second implant material; for example,the osteogenic protein can be a bone morphogenic protein (BMP).Recombinant human BMPs can be used, and may be commercially obtained orprepared as described and known in the art, e.g. in U.S. Pat. No.5,187,076 to Wozney et al.; U.S. Pat. No. 5,366,875 to Wozney et al.;U.S. Pat. No. 4,877,864 to Wang et al.; U.S. Pat. No. 5,108,932 to Wanget al.; U.S. Pat. No. 5,116,738 to Wang et al.; U.S. Pat. No. 5,013,649to Wang et al.; U.S. Pat. No. 5,106,748 to Wozney et al; and PCT PatentNos. WO93/00432 to Wozney et al.; WO94/2693 to Celeste et al.; andWO94/26892 to Celeste et al. The osteogenic protein may be isolated fromtissue sources such as bone. Methods for isolating BMP from bone aredescribed, for example, in U.S. Pat. No. 4,294,753 to Urist and Urist etal., PNAS 371, 1984.

In some embodiments, the osteogenic protein will include a pair ofpolypeptides having amino acid sequences each comprising a sequence thatshares a defined relationship with an amino acid sequence of a referencemorphogenic protein. Desirable osteogenic polypeptides for use in thepresent invention have an amino acid sequence that shares a definedrelationship with a sequence present in osteogenically active humanBMP-2 (SEQ ID NO: 2; see also National Center for BiotechnologicalInformation (NCBI) Accession No. P12643), osteogenically active humanBMP-4 (SEQ ID NO: 4; see also NCBI Accession Nos. P12644, and BAA06410),osteogenically active human BMP-6 (SEQ ID NO: 6; see also NCBI AccessionNo. P22004), or osteogenically active human BMP-7 (SEQ ID NO: 8; seealso NCBI Accession No. P18075). However, any one or more of thenaturally occurring or biosynthetic sequences disclosed herein similarlycould be used as a reference sequence. Polypeptides in a dimeric proteinwith osteogenic activity can each comprise a sequence that correspondsto a reference sequence or that is functionally equivalent thereto.

Functionally equivalent sequences include functionally equivalentarrangements of cysteine residues disposed within the referencesequence, including amino acid insertions or deletions which alter thelinear arrangement of these cysteines, but do not materially impairtheir relationship in the folded structure of the dimeric morphogenprotein, including their ability to form such intra- or inter-chaindisulfide bonds as may be necessary for morphogenic activity.Functionally equivalent sequences further include those wherein one ormore amino acid residues differs from the corresponding residue of areference sequence, e.g., the C-terminal cysteine domain (also referredto herein as the conserved cysteine skeleton) of human BMP-2, providedthat this difference does not destroy bone morphogenic activity.Conservative substitutions of corresponding amino acids in the referencesequence may be used. Amino acid residues that are conservativesubstitutions for corresponding residues in a reference sequence arethose that are physically or functionally similar to the correspondingreference residues, e.g., that have similar size, shape, electriccharge, chemical properties including the ability to form covalent orhydrogen bonds, or the like. Common conservative substitutions are thosefulfilling the criteria defined for an accepted point mutation inDayhoff et al. (1978), 5 Atlas of Protein Sequence and Structure, Suppl.3, ch. 22 (pp. 354-352), Natl. Biomed. Res. Found., Washington, D.C.20007.

Conservative substitutions typically include the substitution of oneamino acid for another with similar characteristics, e.g., substitutionswithin the following groups: valine, glycine; glycine, alanine; valine,isoleucine, leucine; aspartic acid, glutamic acid; asparagine,glutamine; serine, threonine; lysine, arginine; and phenylalanine,tyrosine. The term “conservative variation” also includes the use of asubstituted amino acid in place of an unsubstituted parent amino acidprovided that antibodies raised to the substituted polypeptide alsoimmunoreact with the unsubstituted polypeptide.

As described above, particularly useful sequences for the presentinvention include those comprising the sequences for BMP-2 or BMP-4 (seeWO88/00205, U.S. Pat. No. 5,013,649 and WO91/18098), BMP6 (seeWO90/11366, PCT/US90/01630), and BMP-7 (also referred to as OP1, seeU.S. Pat. No. 5,011,691 and Oppermann et al.), and functionallyequivalent sequences thereto. Publications disclosing these sequences,as well as their chemical and physical properties, include: BMP-2 andBMP-4: WO88/00205, Wozney et al. (1988) Science 242:1528-1534); BMP-7(OP-1): U.S. Pat. No. 5,011,691, U.S. Pat. No. 5,266,683, Ozkaynak etal. (1990) EMBO J. 9: 2085-2093; and BMP-6: Celeste et al. (1991) PNAS87: 9843-9847. Recombinant human BMP-2 (rhBMP-2), recombinant humanBMP-4 (rhBMP-4), recombinant human BMP-6, recombinant human BMP-7(rhBMP-7) or heterodimers thereof, may be used to particular advantage.It will be understood, however, that other BMP proteins may be used inthe present invention, including for example BMP-9.

In other embodiments, useful proteins include biologically activebiosynthetic constructs, including novel biosynthetic morphogenicproteins and chimeric proteins designed using sequences from two or moreknown morphogens.

In certain embodiments, bone morphogenic proteins useful in aspects ofthe invention include those in which the amino acid sequences comprise asequence sharing at least 70% amino acid sequence homology or“similarity”, and preferably 80% homology or similarity, with areference morphogenic protein selected from the foregoing naturallyoccurring proteins. Preferably, the reference protein is human BMP-2,human BMP-4, human BMP-6, or human BMP-7, and the reference sequencethereof is the C-terminal cysteine domain present in osteogenicallyactive forms of these proteins. A polypeptide suspected of beingfunctionally equivalent to a reference morphogen polypeptide can bealigned therewith using the method of Needleman, et al. (1970) J. Mol.Biol. 48:443-453, implemented conveniently by computer programs such asthe Align program (DNAstar, Inc.). Internal gaps and amino acidinsertions in the candidate sequence are ignored for purposes ofcalculating the defined relationship, conventionally expressed as alevel of amino acid sequence homology or identity, between the candidateand reference sequences. “Amino acid sequence homology” is understoodherein to include both amino acid sequence identity and similarity.Homologous sequences share identical and/or similar amino acid residues,where similar residues are conservative substitutions for, or “allowedpoint mutations” of, corresponding amino acid residues in an alignedreference sequence. Thus, a candidate polypeptide sequence that shares70% amino acid homology with a reference sequence is one in which any70% of the aligned residues are either identical to, or are conservativesubstitutions of, the corresponding residues in a reference sequence. Ina currently preferred embodiment, the reference sequence is BMP-2. Bonemorphogenic proteins useful herein accordingly include allelic,phylogenetic counterpart and other variants of the preferred referencesequence, whether naturally-occurring or biosynthetically produced(e.g., including “muteins” or “mutant proteins”), as well as novelmembers of the general morphogenic family of proteins, including thoseset forth and identified above. Certain particularly preferredmorphogenic polypeptides share at least 60% amino acid identity with thepreferred reference sequence of human BMP-2, still more preferably atleast 80% amino acid identity therewith.

In still other embodiments, useful osteogenically active proteins havepolypeptide chains with amino acid sequences comprising a sequenceencoded by a nucleic acid that hybridizes, under any or all of low,medium or high stringency hybridization conditions, to DNA or RNAencoding reference morphogen sequences, e.g., C-terminal sequencesdefining the conserved seven cysteine domains of BMP-2 (SEQ. ID NO. 1;see also NCBI Accession No. NM001200), BMP-4 (SEQ. ID NO. 3; see alsoNCBI Accession Nos. NM001202; NM130850; and NM130851), BMP-6 (SEQ. IDNO. 5; see also NCBI Accession No. NM001718) or BMP-7 (SEQ. ID NO. 7;see also NCBI Accession No. NM001719), and the like. As used herein,high stringent hybridization conditions are defined as hybridizationaccording to known techniques in 40% formamide, 5×SSPE, 5×Denhardt'sSolution, and 0.1% SDS at 37° C. overnight, and washing in 0.1×SSPE,0.1% SDS at 50° C. Standard stringency conditions are well characterizedin commercially available, standard molecular cloning texts. See, forexample, Molecular Cloning A Laboratory Manual, 2nd Ed., ed. bySambrook, Fritsch and Maniatis (Cold Spring Harbor Laboratory Press:1989); DNA Cloning, Volumes I and II (D. N. Glover ed., 1985);Oligonucleotide Synthesis (M. J. Gait ed., 1984): Nucleic AcidHybridization (B. D. Hames & S. J. Higgins eds. 1984); and B. Perbal, APractical Guide To Molecular Cloning (1984).

Proteins useful in the present invention generally are dimeric proteinscomprising a folded pair of polypeptides. Such morphogenic proteins areinactive when reduced, but are active as oxidized homodimers and whenoxidized in combination with others of this invention to produceheterodimers. Thus, members of a folded pair of morphogenic polypeptidesin a morphogenically active protein can be selected independently fromany of the specific polypeptides mentioned above.

Bone morphogenic proteins useful in the invention include proteinscomprising any of the polypeptide chains described above, whetherisolated from naturally-occurring sources, or produced by recombinantDNA or other synthetic techniques, and includes allelic and phylogeneticcounterpart variants of these proteins, as well as muteins thereof, andvarious truncated and fusion constructs. Deletion or addition mutantsalso are envisioned to be active, including those that may alter theconserved C-terminal cysteine domain, provided that the alteration doesnot functionally disrupt the relationship of these cysteines in thefolded structure. Accordingly, such active forms are considered theequivalent of the specifically described constructs disclosed herein.The proteins may include forms having varying glycosylation patterns,varying N-termini, a family of related proteins having regions of aminoacid sequence homology, and active truncated or mutated forms of nativeor biosynthetic proteins, produced by expression of recombinant DNA inhost cells.

The bone morphogenic proteins contemplated herein can be expressed fromintact or truncated cDNA or from synthetic DNAs in prokaryotic oreukaryotic host cells, and purified, cleaved, refolded, and dimerized toform morphogenically active compositions. Candidate host cells include,without limitation, prokaryotes including E. coli, or eukaryotesincluding yeast, or mammalian cells, such as CHO, COS or BSC cells. Oneof ordinary skill in the art will appreciate that other host cells canbe used to advantage. Detailed descriptions of specific bone morphogenicproteins useful in the practice of this invention, including how tomake, use and test them for osteogenic activity, are disclosed innumerous publications, including for example those referencedhereinabove. Additional osteogenic proteins that may be used in aspectsof the present invention are included in the group of osteogenicproteins identified in U.S. patent application Ser. No. 09/045,331 filedMar. 20, 1998, published Aug. 23, 2001 as US 20010016646 A1.

Other therapeutic growth factors may also be used in accordance with thepresent invention, especially those that may be used to stimulate boneformation. Such proteins are known and include, for example,platelet-derived growth factors, insulin-like growth factors,cartilage-derived morphogenic proteins, growth differentiation factorssuch as growth differentiation factor 5 (GDF-5), and transforming growthfactors, including TGF-α and TGF-β.

Thus, in view of this disclosure and the knowledge available in the art,skilled genetic engineers can isolate genes from cDNA or genomiclibraries of various different biological species, which encodeappropriate amino acid sequences, or construct DNAs fromoligonucleotides, and then can express them in various types of hostcells, including both prokaryotes and eukaryotes, to produce largequantities of active proteins capable of stimulating endochondral bonemorphogenesis in a mammal.

In one mode of preparing osteogenic implants of the invention, thesecond implant material can be positioned over a surface of a body ofthe first implant material, either before or after the osteogenicprotein has been incorporated into the second implant material. Forexample, a sheet of the second implant material having the osteogenicprotein incorporated therein can be wrapped around a block or othersubstantial three dimensional volume of the first implant material, toprepare an osteogenic implant of the invention. In certain modes ofpracticing the invention, the osteogenic implant including thecombination of the first and second resorbable implant materials can besized for receipt at a location between two adjacent vertebrae of amammal, including a human, and can be configured to facilitate fusion ofthe two vertebrae. In one specific embodiment, the osteogenic implant isconfigured for insertion between adjacent transverse processes of ahuman patient, e.g. in the lumbar spine, so as to occupy the spatialvolume therebetween with the second material incorporating theosteogenic protein in contact with the transverse processes. Implants soconfigured can be effectively used to achieve posterolateral fusion inhuman or other patients in need thereof, including lumbar posterolateralfusion. Such posterolateral fusion procedures can be performed as opensurgical procedures or minimally invasive procedures, and can beinstrumented or non-instrumented. Minimally invasive procedures can befacilitated by specialized systems, such as the CD Horizon® Sextantpercutaneous rod insertion system available from Medtronic SofamorDanek.

Implants of the invention can also be used in other spinal fusionprocedures including anterior and posterior lumbar spinal fusionprocedures. For example, implants of the invention can be used on thelamina in posterior fusion or within the disc space, e.g. in interbodyfusion techniques. Relatedly, implants of the invention can be used inconjunction with load bearing spinal implants such as fusion cages, andmay serve to induce bone growth in, through and/or around such loadbearing spinal implants.

Still further, implants of the invention can be used to promote bonegrowth from and between bone surfaces in other areas of the body,including for example in the repair of long bone defects or cranialdefects, including but not limited to the repair of simple and compoundfractures and non-unions.

With reference now to FIGS. 1-3, an illustrative osteogenic implant 11of the invention will be described. Osteogenic implant 11 includes afirst implant material 12 forming an implant body for occupying asubstantial three-dimensional volume through which bone growth isdesired. First implant material 12 can, for example, have a height h¹ ofabout 1 cm to about 10 cm, a width w¹ of about 0.5 cm to about 2 cm, anda thickness t¹ of about 0.5 cm to about 1.5 cm. Implant 11 also includesa second implant material 13 generally in sheet form, that is used tocover at least a portion of the outer surface of implant material 12 andcan in certain embodiments completely encase and cover all surfaces ofimplant material 12. As illustrated in FIG. 1, sheet form implantmaterial 13 can be folded around implant material 12 (see arrows) toform an osteogenic implant of the present invention including combinedfirst and second matrix materials. Implant material 13 can have suitabledimensions for this purpose, for example having a height h² of about 1cm to about 10 cm, a width w² of about 1 cm to about 10 cm, and athickness t² of about 0.2 cm to about 0.5 cm. Unless stated otherwise,the dimensions given herein for the first implant material 12 and thesecond implant material 13 are their dimensions when wet (saturated).

With particular reference now to FIG. 2, shown is implant 11 of theinvention including first implant material 12 encased by implantmaterial 13. Implant material 12 in the illustrated embodiment includesa matrix forming material 14 and mineral particles 15 embedded therein.Second implant material 13 is shown wrapped around first implantmaterial 12 forming an interface I¹ therebetween. In the illustratedembodiment, second implant material 13 wraps completely around firstimplant material 12 and contacts itself at interface I². In accordancewith aspects of the present invention, second implant material 13 willbe impregnated with a liquid carrier including an osteogenic proteinsuch as a BMP, and first implant material 12, at least as the implant 11is assembled, will be free or substantially free from the osteogenicprotein incorporated in second implant material 13. It is expected inthis regard that once implant 11 is assembled, some level of diffusionof osteogenic protein across interface I¹ may occur; however, in certainembodiments of the invention, it is nonetheless expected that at least asubstantial internal volume of the implant body formed from firstimplant material 12 will remain essentially free from any suchosteogenic protein and will be osteoconductive and not osteoinductive innature. As well, in the illustrated embodiment, first implant material12 contains mineral particles 15, whereas second implant material 13 isfree of mineral particles, while the matrix forming material of implantmaterials 12 and 13 may be the same, e.g., collagen. In such anarrangement, the first implant material 12 can be more resistant tocompressive forces than second implant material 13, with both structuresmaintaining three-dimensional stability and a flexible or pliablenature. Such implants are advantageously facile in use, and ineffectively utilizing osteogenic proteins such as BMPs dosed to thepatient with implant 11.

Referring now to FIG. 3, shown are two osteogenic implants 11 of theinvention in a schematic representation wherein they can facilitateposterolateral fusion in a human patient. A bilateral fusion is shown,between a first vertebra V¹ and a second vertebra V². In such aprocedure, a first osteogenic implant 11 traverses the space between atransverse process TP^(1a) of V¹ and transverse process TP^(2a) of V². Asimilar arrangement is shown on the opposite side wherein an implant 11contacts transverse process TP^(1b) of the V¹ and transverse processTP^(2b) of vertebrae V², and traverses the space therebetween.Osteogenic implants 11 thereby induce bone growth from the surfaces ofthe contacted transverse processes, which bone growth effectivelyextends through the volume occupied by the osteogenic implants 11,resulting in arthrodesis of the transverse processes and fusion ofvertebrae V¹ with vertebrae V². If desired, for such procedures thesurfaces of the involved transverse processes may be decorticated tofacilitate the fusion process. Techniques and implements fordecortication are well known to those of ordinary skill in the art andcan be used within the scope of the invention.

The dimensions of implant bodies formed from the first implant materialmay vary depending on the application. For posterolateral fusion devicesfor humans, these dimensions may for example be about 3 cm to about 6 cmin height (h¹), about 1 cm to about 2 cm in width (w¹), and about 0.5 toabout 1.5 cm in thickness (t¹). The dimensions for the second implantmaterial may likewise vary. Illustrative implant devices forposterolateral fusion for humans can include an implant body of thefirst implant material sized as noted above, combined with a secondimplant material having a height (h²) of about 3 cm to about 6 cm, awidth (w²) of about 3 to about 7 cm, and a thickness (t²) of about 0.2cm to about 0.5 cm. The total volume of implant material (first plussecond implant material) for human posterolateral fusion implants willbe sufficient to provide the desired fusion mass (e.g. including onelevel or two level fusions), and may for example range from about 5cubic centimeters (cc's) to about 20 cc's when the implant materials arewet (saturated).

In this same vein, the total dose of osteogenic protein included in anosteogenic implant of the invention will be sufficient to induce thedesired bone growth through the volume occupied by the implant. In aposterolateral fusion implant, the total dose of osteogenic protein willbe sufficient to induce the desired intertransverse process fusion massin combination with the implant, and in the case of a bone morphogenicprotein such as BMP-2 (including recombinant human BMP-2, rhBMP-2) thistotal dose may for example not exceed about 12 mg, e.g. typically rangefrom about 1 mg to about 12 mg, more typically about 3 mg to about 9 mg,including in human fusions. As noted above, this dosed amount ofosteogenic protein may be distributed regionally within the implantmaterial. Thus, all or substantially all of this dosed protein may becarried by the second implant material; or, in certain otherembodiments, the second implant material may carry a concentration (mgper cc of implant material) that is higher than the concentrationcarried by the first implant material. In any case, the osteogenicprotein may be substantially homogeneously distributed through the firstand/or second implant material, or may be regionally concentrated withinthe implant material, e.g. as a coating.

It will be understood that implants of the invention may also includemore than one piece of the first or second implant material. Forexample, multiple pieces of the first implant material may be wrappedwithin a single piece of the second implant material, or multiple piecesof the second implant material may cover various portions of the surfaceof a monolithic implant body formed from the first implant material.Illustratively, separate pieces of the second implant material carryingthe osteogenic protein may be positioned overtop a monolithic body ofthe first implant material and positioned to contact bone surfaces to befused.

Another embodiment of the invention, in which the first implant materialis provided as multiple pieces rather than a single piece, is shown inFIG. 4. In particular, implant construct 20 includes a first (inner)implant material constituted by a plurality of discrete ceramic granules21, for example synthetic biphasic calcium phosphate granules 21. Thesegranules are present in sufficient quantity to occupy a desiredthree-dimensional volume into which bone growth is desired, for examplea volume into which a spinal fusion mass such as an interbody fusionmass or a posterolateral fusion mass. Granules 21 provide the firstimplant material, which is wrapped within a second (outer) implantmaterial 22 which is preferably provided by a porous sponge matrix,especially a porous collagen sponge matrix. The second implant materialcarries an osteogenic protein such as a BMP. In certain embodiments, anaqueous formulation including the BMP or other osteogenic protein isused to wet the first implant material, such that the formulation issorbed into the implant material. The implant construct 20 canthereafter be implanted into a patient so that the second implantmaterial 22 carrying the osteogenic protein contacts bone surfaces to befused together, whereupon the growth of a fusion bone mass is induced.In one embodiment, implant construct 20 can be configured forposterolateral spinal fusion, having a length sufficient to traverse thespinous processes to be fused.

One particularly advantageous implant that can be used for human spinalfusion, including posterolateral fusion, has a BMP such as rhBMP-2 in aliquid solution dispersed substantially homogeneously through the secondimplant material to provide a concentration of at least about 0.4 mg/ccbased upon the wet (saturated) volume of the implant, more preferably atleast about 0.6 mg/cc, e.g. in the range of about 0.6 mg/cc to about 4mg/cc, with the first implant material being free from the osteogenicprotein other than that which might diffuse from the second materialinto the first material upon contact between the two materials, e.g.during preparation, implantation or residence in the patient. Suchimplants can be prepared, for instance, by infusing the second implantmaterial with a solution of the osteogenic protein and thereafterpositioning it around the first implant material.

In certain embodiments, measures are taken to localize the majority ofthe osteogenic protein to the second (outer) implant material andminimize substantial diffusion therefrom that might deleteriously reducethe concentration of osteogenic protein (in mg per cc of wet implantmaterial) in the outer regions of the overall implant that contact andinitiate bone growth from adjacent bone surfaces. For example, thesecond implant material can be effective to bind the BMP or otherosteogenic protein by ionic and/or hydrogen bonding or other bondingforces. For example, collagenous sponge material exhibits the capacityto bind BMPs such as BMP-2 in a non-covalent fashion, and the amount ofprotein that is effectively retained by the material against fusion orwash-out increases over the time of contact with an aqueous BMPformulation. Thus, embodiments of the invention are provided wherein anaqueous formulation of the BMP or other osteogenic protein is applied tothe second implant material and allowed to equilibrate for a period oftime prior to contact with the first implant material. Thisequilibration period can last for at least about 2 minutes, at leastabout 5 minutes, and is typically in the range of about 5 to about 30minutes.

The equilibration or other protein retaining technique will desirablymaintain at least about 70% by weight of the BMP or other osteogenicprotein localized to the second implant material at least during themanipulation and implantation of the combined implant construct into thepatient. In certain embodiments, at least about 80% by weight of theosteogenic protein will be so retained, even at least about 90% or more.It will thus be understood that certain amounts of the osteogenicprotein may migrate from the second implant material in theseembodiments, including for example some level of diffusion into thefirst implant material; however, in these embodiments any amount ofosteogenic protein in the first implant material due to diffusion orotherwise will be relatively low compared to that in the second implantmaterial, and the osteogenic protein applied to the second implantmaterial will be substantially retained therein at least to the point ofimplant as discussed above. In this manner, an effective, high spatialconcentration of the BMP or other osteogenic protein can be maintainedat the outer regions thereof sufficient to stimulate bone ingrowth frombone surfaces that are contacted.

The present invention also includes kits for promoting bone growth inpatients, wherein the kits include a first implant material as describedherein, a second implant material as described herein, and an osteogenicprotein as described herein. Each of such components of the kit may beprovided for example in a lyophilized or otherwise dry state, or in awet state. The kits can include a structural element in which thecomponents are stably held spaced from one another, in a sterile,medically acceptable packaging system. Such kits can likewise includeinstructions for use of the kit components for promoting bone growthwithin a patient, for example a spinal fusion procedure such as aposterolateral spinal fusion procedure. Kits of the invention can thusalso include other components such as syringes, vials, surgicalinstruments for minimally invasive or open techniques, spinal rods,spinal cages or other load-bearing interbody fusion devices, spinalplates, bone screws, and the like.

The invention will now be described with reference to certain specificExamples. It will be understood that these Examples are illustrative andnot limiting of the invention.

Example 1 Preparation of Collagen Sponge/Bone Particle Composite

12 grams of biphasic calcium phosphate particles (containing 85%tricalcium phosphate and 15% hydroxyapatite), 1 mm in diameter, areadded to 12 grams of collagen slurry (0.192 grams of collagen). Thiscomposite slurry is poured into a 7.5 cm×10.0 cm mold, freeze dried,double sterile packaged, and sterilized by ETO gas sterilization.

Example 2 Posterolateral Fusions Using Combined Matrix Implants 2.1Materials and Methods

The entire protocol for this Example was reviewed and approved by theInstitutional Animal Care and Use Committee for Emory University.

2.1.1 Surgical Procedure

Nine skeletally mature rhesus macaques underwent single levelposterolateral intertransverse process spinal arthrodesis under generalanesthesia. Anesthesia was induced with 3-5 mg/kg of intramuscular orsubcutaneous telazol, and maintained with 1%-2% inhalational halothane.The monkeys were placed prone on the operating table with chestsupports, then shaved, prepped and draped in a sterile manner for lumbarsurgery.

A manual palpation of the iliac crests was used to estimate the L4-5vertebral level using a preoperative lateral plain film. Subsequently,10 mL of bupivicane was used to infiltrate the lumbodorsal region, and amidline incision was made to expose the lumbodorsal fascia.

Bilateral fascial incisions were made approximately 2-3 cm off themidline, and a Wiltse muscle-splitting technique was used to develop theplane between the multifidous and logissiumus muscles. The transverseprocesses of L4 and L5 and the intertransverse membrane were exposed,while leaving the facet joints intact. The dorsal aspects of the L4 andL5 transverse processes were decorticated using a high-speed burr, untilbleeding surfaces with cancellous bone were noted. Graft materials (seebelow) were then placed in the paraspinal muscle bed between thetransverse processes. Absorbable 3-0 sutures were used to close thefascia, and the skin was closed using both staples and 3-0 absorbablesutures.

Animals received 0.1 mg/kg bupinorphine when indicated for postoperativepain control and were individually housed. There was no postoperativerestriction on activity and no supportive orthotic devices were used.The monkeys were fed a regular diet on a routine basis for the animalfacility.

Recombinant human bone morphogenic protein-2 (rhBMP-2) (MedtronicSofamor Danek, Memphis Tenn.) was delivered from a stock concentrationof 1.5 or 3.0 mg/mL. The compression resistant matrix (CRM) (MedtronicSofamor Danek, Memphis Tenn.) was comprised of a bovine type I collagensponge impregnated with 15% hydroxyapatite/85% tricalcium phosphateceramic granules, and was prepared generally as described in Example 1.The CRM block was 3.5 cm in height, and 1.2 cm in both width andthickness. The total volume of the CRM implant was about 5.0 cc. Thedimensions of the dry absorbable collagen sponge (Medtronic SofamorDanek, Memphis, Tenn.) were 5×3.8×0.35 cm.

The animals were divided into three groups (n=3 for each group) and hadone of the following graft configurations implanted bilaterally asdescribed above: 1) rhBMP-2 (10 mg per side) delivered directly on theCRM carrier; 2) rhBMP-2 (3 mg/side) delivered directly on the CRMcarrier; and 3) rhBMP-2 (3 mg/side) delivered on the absorbable collagensponge, allowed to equilibrate for about 15 minutes, and then wrappedaround a block of CRM carrier.

2.1.2 Assessment of Spine Fusion

All animals were euthanized at 24 weeks postoperatively with intravenouspentobarbital. Subsequently, the lumbar spines were removed, andarthrodesis was assessed blindly by 4 methods: 1) manual palpation, 2)posteroanterior plain radiographs, 3) computerized tomography (CT), and4) undecalcified histology.

After harvesting, the lumbar spines were manually palpated at the levelof attempted fusion by a blinded observer. The observer also palpatedthe superior and inferior adjacent motion segments. Each motion segmentwas considered fused only if there was no motion present, otherwise itwas graded as not fused.

Radiographs of each spine were made using a tube to plate distance of 90cm. The radiographs were then reviewed in a blinded method; only thoseradiographs showing a continuous pattern of trabecular bone in theintertransverse fusion mass were graded as fused.

All lumbar spine specimens underwent CT scans in the region of thearthrodesis. A high speed spiral CT scanner (GE, Milwaukee, Wis.) wasutilized, using the following parameters: 100 cm field of view, 150 mA,100 kV, 1 mm gap, and 1 mm slice thickness. The continuity of the fusionmass and any bone formation outside the fusion mass were evaluated.

Histologic analysis was performed after the lumbosacral spines werefixed for 24 hours in a 10% neutral-buffered solution. The specimenswere then placed in 70% ethanol, trimmed, and sequentially dehydrated in95% and 100% ethanol. This step was followed by a xylene treatment. Thespecimens were then divided in half in the midsagittal plane, embeddedin methylmethacrylate, and sectioned to 25 micrometer thickness in asagittal or coronal plane using an automated system Exakt Technologies,Inc., Oklahoma City, Okla.). The sections were stained with 1% methyleneblue and 0.3% basic fuchsin. The sections were then evaluated for thepresence of newly formed trabecular bone. Histologic fusion wasconsidered to be present if there was continuous new bridging boneacross the carrier connecting the two transverse processes.

2.2 Results

2.2.1 Manual Palpation

All animals survived surgery and had uneventful postoperative courses.The three monkeys that received 10 mg of rhBMP-2 on the CRM carrierachieved solid fusions. The three monkeys that had 3 mg rhBMP-2implanted on the CRM carrier did not achieve solid fusions. The threemonkeys that received 3 mg rhBMP-2 on the absorbable collagen spongewhich was then wrapped around the CRM carrier achieved solid fusions.

2.2.2 Radiographs

Serial plain radiographs were taken at 4-6 week intervals and confirmedthe manual palpation results. Early fusion masses were visible on theplain films by 12 weeks and by 8 weeks on CT scans in most cases. Theserial CT scan results also paralleled the plain radiographs. It wasmuch easier to interpret the presence and extent of new bone formationin the posterolateral spine using CT scans. The three monkeys that didnot achieve solid fusions with the 3 mg rhBMP-2 placed directly on theCRM carrier showed some spotty bone formation, especially around thedecorticated transverse processes, but it was minimal and not nearlyenough to form a continuous bridge of bone.

2.2.3 Histology

Histologic analysis of the fusion masses demonstrated consistentfindings with the CT scans. Normal appearing mature trabecular bone waspresent with marrow cavities in the six monkeys with solid spinefusions. There was no evidence of abnormal inflammatory cells or otherreaction to the carrier. In the six animals with the solid fusions, theCRM carrier had been completely remodeled. In the three animals with thenonunions, most of the CRM carrier had been resorbed.

Example 3 Medical Kit and Preparation of Combined Implant MaterialConstructs

A medical kit is provided including a vial containing sterilelyophilized rhBMP-2 (12 mg); a collagen sponge (Absorbable CollagenSponge (ACS), Integra Lifesciences) 3″×4″ in size (7.5 cm×10 cm)packaged in a tray; a vial containing sterile water for injection (10ml); two 10 ml syringes; two 20 G 1½%″ needles; and instructions as tothe following preparation.

Using one of the needles and a 10 ml syringe, the rhBMP-2 isreconstituted with 8.4 ml of sterile water for injection in a vial. TherhBMP-2 is gently swirled in the vial during reconstitution. The ACS iscut in half making two pieces each dimensioned 2″×3″. The ACS is placedin the packaging tray. Using a second needle and 10 ml syringe, 4 ml ofrhBMP-2 are withdrawn from the vial. 4 ml of rhBMP-2 solution isdistributed onto one 2″×3″ piece of ACS. The second needle/syringe isused to withdraw another 4 ml of the rhBMP-2 solution from the vial,which is distributed uniformly onto the second piece of ACS. The ACSpieces are allowed to stand for a minimum of 15 minutes (and should beused for implantation within the next 60 minutes). A 10 cc vial ofMasterGraft™ granules (10 cc, biphasic calcium phosphate having an 85:15tricalcium phosphate:hydroxyapatite ratio) is divided into two equal 5cc portions. The 5 cc granule portions are each distributed onto one ofthe 2″×3″ wetted ACS pieces. Using forceps, the rhBMP-2 soaked ACS withMasterGraft™ granules are each rolled into a 2″ wide roll with the ACSsurrounding the MasterGraft granules. The combined implant constructs soprepared can be used in a spinal interbody fusion procedure, potentiallyin combination with metal cages into which the constructs are inserted,or in a posterolateral spinal fusion procedure.

While the invention has been illustrated and described in detail in theforegoing description, the same is to be considered as illustrative andnot restrictive in character, it being understood that only certainembodiments have been shown and described and that all changes andmodifications that come within the spirit of the invention are desiredto be protected. In addition, all publications cited herein are herebyincorporated by reference in their entirety as if each had beenindividually incorporated by reference and fully set forth.

1. An osteogenic implant for promoting bone growth between first andsecond bone surfaces, comprising: a first resorbable implant materialdefining an implant body configured for receipt between the first andsecond bone surfaces, said first resorbable implant material comprisinga porous collagenous matrix containing mineral particles, said implantbody having an outer surface; the first resorbable implant materialbeing substantially free of an osteogenic protein; a second resorbableimplant material wrapped around at least a portion of said outer surfaceof said implant body and positioned to contact said first and secondbone surfaces; and an osteogenic protein carried by said secondresorbable implant material.
 2. (canceled)
 3. The osteogenic implant ofclaim 1, wherein: said osteogenic protein is a bone morphogenic protein(BMP).
 4. The osteogenic implant of claim 3, wherein: said BMP is BMP-2or BMP-7.
 5. The osteogenic implant of claim 4, wherein: said BMP isBMP-2.
 6. The osteogenic implant of claim 5, wherein: said BMP-2 isrecombinant human BMP-2.
 7. (canceled)
 8. The osteogenic implant ofclaim 1, wherein: said osteogenic protein is BMP-2.
 9. The osteogenicimplant of claim 8, wherein: said BMP-2 is recombinant human BMP-2. 10.The osteogenic implant of claim 1, wherein: said mineral particlescomprise bone.
 11. The osteogenic implant of claim 1, wherein: saidmineral particles comprise synthetic ceramic.
 12. The osteogenic implantof claim 11, wherein: (i) said synthetic ceramic comprises tricalciumphosphate or (ii) said synthetic ceramic comprises biphasic calciumphosphate.
 13. (canceled)
 14. The osteogenic implant of claim 12,wherein: said biphasic calcium phosphate has a weight ratio oftricalcium phosphate to hydroxyapatite of about 50:50 to about 95:5. 15.The osteogenic implant of claim 14, wherein: said ratio of tricalciumphosphate to hydroxyapatite is about 80:20 to about 90:10.
 16. Theosteogenic implant of claim 15, wherein: said ratio of tricalciumphosphate to hydroxyapatite is about 85:15.
 17. The implant of claim 29,wherein: the osteogenic protein is BMP-2 and the mineral comprisestricalcium phosphate and hydroxyapatite in a ratio of about 85:15. 18.(canceled)
 19. (canceled)
 20. The osteogenic implant of claim 1,wherein: said second resorbable implant material comprises a collagenoussponge.
 21. (canceled)
 22. (canceled)
 23. An implant configured topromote posterolateral spinal fusion between first and second transverseprocesses in a patient, comprising: a first resorbable implant materialconfigured for receipt between the first and second transverseprocesses, said first resorbable implant material comprising mineralparticles, said implant material having an outer surface; a collagensponge carrier wrapped around at least a portion of said outer surfaceof said implant material and positioned to contact the first and secondtransverse processes; and a bone morphogenic protein (BMP) incorporatedin said collagen sponge carrier.
 24. The implant of claim 23, wherein:said collagen sponge carrier comprises the BMP at a concentration ofabout 0.6 mg/cc to about 4 mg/cc; and at least a portion of said implantmaterial is essentially free from said BMP.
 25. (canceled) 26.(canceled)
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 28. (canceled)
 29. An implant for promotingbone growth, comprising: a first bioresorbable implant materialcomprising mineral and configured to occupy a volume for bone ingrowth;and a second bioresorbable implant material comprising a porous collagensponge matrix wrapped around at least a portion of said first implantmaterial; said medical implant comprising an osteogenic factor. 30.(canceled)
 31. (canceled)
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 42. The implant of claim 29,wherein the first bioresorbable implant material is a ceramic block. 43.(canceled)
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